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Acute Renal Failure

Acute Renal Failure

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Acute Renal Failure

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  1. Acute Renal Failure Matthew L. Paden, MD Pediatric Critical Care Emory University Children’s Healthcare of Atlanta at Egleston

  2. Structure and Function of the Kidney • Primary unit of the kidney is the nephron • 1 million nephrons per kidney • Composed of a glomerulus and a tubule • Kidneys receive 20% of cardiac output Renal Lecture Required Picture #1

  3. Renal blood flow • Aorta  Renal artery  interlobar arteries  interlobular arteries  afferent arterioles  glomerulus  efferent arterioles • In the cortex  peritubular capillaries • In the juxtamedullary region vasa recta • Back to the heart through the interlobular  intralobar  renal veins

  4. Glomerular Filtration Rate • Determined by the hydrostatic and oncotic pressure within the nephron • Hydrostatic pressure in the glomerulus is higher than in the tubule, so you get a net outflow of filtrate into the tubule • Oncotic pressure in the glomerulus is the result of non-filterable proteins • Greater oncotic pressure as you progress through the glomerulus • GFR = Kf (hydrostatic – oncotic pressure)

  5. Renal Lecture Required Picture #2

  6. Glomerular Filtration Rate • The capillary endothelium is surrounded by a basement membrane and podocytes • Foot processes of the podocytes form filtration slits that : • Allow for ultrafiltrate passage • Limit filtration of large negatively charged particles • Less than 5,000 daltons = freely filtered • Large particles (albumin 69,000 daltons) not filtered

  7. Tubular Function • Proximal • Most of reabsorption occurs here • Fluid is isotonic with plasma • 66-70% of sodium presented is reabsorbed • Glucose and amino acids are completely reabsorbed

  8. Tubule Function • Loop of Henle • Urine concentration and dilution via changes in oncotic pressure in the vasa recta • Descending tubule – permeable to water, impermeable to sodium • Ascending tubule – actively reabsorbs sodium, impermeable to water

  9. Tubular Function • Medullary thick ascending limb – critical for urinary dilution and most often damaged in ARF • ADH stimulates Na re-absorption in this area • Most sensitive to ischemia • Low oxygen tension, high oxygen consumption • Lasix use here inhibits the Na-K-2Cl ATPase which in the face of ARF, may decrease oxygen consumption and ameliorate the severity of the ARF

  10. Tubular Function • All of those studies done in an in vitro model • In vivo, if you drop oxygen concentration even sub-atmospheric you do not get tubular damage even with increased tubular workload • In vivo models exist where you do see that damage, but appears to need a “second hit”

  11. Tubule Function • Distal Tubule • Re-absorption of another ~12% of NaCl • Proximal segment – impermeable to water • Distal segment is the cortical collecting duct and secretes K and HCO3

  12. Tubular Function • Collecting Duct • Aldosterone acts here to increase Na reuptake and K wasting • ADH enhances water re-absorption • Urea re-absorption to maintain the medullary interstitial concentration gradient

  13. Acute Renal Failure - Definitions • Renal failure is defined as the cessation of kidney function with or without changes in urine volume • Anuria – UOP < 0.5 cc/kg/hour • Oliguria – UOP “more than 1 cc/kg/hour” • Less than?

  14. Acute Renal Failure - Definitions • 70% Non-oliguric , 30% Oliguric • Non-oliguric associated with better prognosis and outcome • “Overall, the critical issue is maintenance of adequate urine output and prevention of further renal injury.” • Are we converting non-oliguric to oliguric with our hemofilters?

  15. Acute Renal Failure - Diagnosis • Pre-renal • Decrease in RBF constriction of afferent arteriole which serves to increase systemic blood pressure by reducing the “shunt” through the kidney, but does so at a cost of decreased RBF • At the same time, efferent arteriole constricts to attempt to maintain GFR • As GFR decreases, amount of filtrate decreases. Urea is reabsorbed in the distal tubule, leading to increased tubular urea concentration and thus greater re-absorption of urea into the blood. • Creatinine cannot be reabsorbed, thus leading to a BUN/Cr ratio of > 20

  16. Pre-Renal vs. Renal Failure Renal Lecture Required Picture #3

  17. Acute Renal Failure - Diagnosis • Diagnosis • Ultrasound • Structural anomalies – polycystic, obstruction, etc. • ATN – • poor corticomedullary differentiation • Increased Doppler resistive index • (Systolic Peak – Diastolic peak) / systolic peak • Nuclear medicine scans • DMSA – Static - anatomy and scarring • DTPA/MAG3 – Dynamic – renal function, urinary excretion, and upper tract outflow

  18. Acute Renal Failure • Overall, renal vasoconstriction is the major cause of the problems in ARF • Suggested ARF be replaced with vasomotor nephropathy • Insult to tubular epithelium causes release of vasoactive agents which cause the constriction • Angiotensin II, endothelin, NO, adenosine, prostaglandins, etc.

  19. Regulation of Renal Blood Flow • In adults auto-regulated over a range of MAP’s 80-160 • Developmental changes • Doubling of RBF in first 2 weeks of life • Triples by 1 year • Approaches adult levels by preschool • Renal blood flow regulation is complex • No one system accounts for everything…..

  20. Renin-Angiotensin Axis • For the one millionth time…. • Hypovolemia leads to decreased afferent arteriolar pressure which leads to decreased NaCl re-absorption which leads to decreased Cl presentation to the macula densa which increases the amount of renin secreted from the JGA which increases conversion angiotensinogen to AGI to AGII which increases Aldosterone secretion from the adrenal cortex and ADH which leads to increased sodium and thus water re-absorption from the tubule which increases your blood pressure……whew…

  21. Renin Angiotensin Axis Renal Lecture Required Picture #4

  22. Renin Angiotensin Axis • Renin’s role in pathogenesis of ARF • Hyperplasia of JGA with increased renin granules seen in patients and experimental models of ARF • Increased plasma renin activity in ARF patients • Changing intra-renal renin content modifies degree of damage • Feed animals high salt diet (suppress renin production)  renal injury  less renal injury than those fed a low sodium diet

  23. Renin Angiotensin Axis • Not the only thing going on though • You can also ameliorate renal injury by induction of solute diuresis with mannitol or loop diuretics (neither affect the RAS) • No change in renal injury in animals given ACE inhibitors, competitive antagonist to angiotensin II • Overall, role of RAS in ARF is uncertain

  24. Prostaglandins • PGE 2 and PGI • Very important for renal vasodilation, especially in the injured kidney • Act as a buffer against uncontrolled A2 mediated constriction • If you constrict the afferent arteriole, you will decrease GFR • The RAS and Prostaglandin pathways account for ~60% of RBF auto-regulation…

  25. Adenosine • Potent renal vasoconstrictor • Peripheral vasodilator • Infusion of methylxanthines (adenosine receptor blockers) inhibits the decrease in GFR that is seen with tubular damage • Some animal models show that infusion of methylxanthines lessen renal injury in ARF

  26. Adenosine • But…. Likely not a major factor in ARF • Methylxanthines have lots of other actions besides adenosine blockade • Adenosine is rapidly degraded after production • Intra-renal adenosine levels diminish very rapidly after reperfusion, but the vasocontriction remains for a longer period • Finally, if you block ADA, creating higher tissue adenosine levels, and then create ischemia  you actually get an enhancement of renal recovery

  27. Endothelin • 21 amino acid peptide that is one of the most potent vasoconstrictors in the body • Can be used as a pressor • Its role in unclear in normal state • In ARF, overproduction by cells (both in and outside of the kidney) leads to decreased afferent flow and thus decreased RBF and GFR • Endothelin increases mesangial cell contraction which reduces glomerular ultrafiltration • Stimulates ANP release at low doses and can increase UOP • Anti-endothelin antibodies or endothelin receptor antagonists decrease ARF in experimental models

  28. Nitric Oxide • Produced by multiple iso-enzymes of NOS • In addition to its role in vasodilation, likely has a role in sodium re-absorption • Give a NOS blocker and you get naturesis • Important in the overall homeostasis of RBF • Exact mechanisms not worked out completely…at least when Rogers was written….

  29. Obligatory Incomprehensible Pathway for Jim #1

  30. Nitric Oxide • Confusing results • Ischemic rat kidney model – inducing NOS causes increasing injury • Hypoxic tubular cell culture model – inducing NOS causes increasing injury • But if you block NOS production, you get worsening of renal function and severe vasoconstriction

  31. Nitric Oxide • So stimulation of NO in the renal vasculature will modulate vasoconstriction and lead to lesser injury…but… • That same induction of NO in the tubular cells will cause increased cytotoxic effects

  32. Dopamine • Dopamine receptors in the afferent arteriole • Dilation of renal vasculature at low doses, constriction at higher doses • Also causes naturesis (? Reason for increased UOP after starting) • Renal dose dopamine controversy……….

  33. Renal Hemodynamics and ARF • Conclusions…. • Renal vasoconstriction is a well documented cause of ARF • Renal vasodilation does not consistently reduce ARF once established • Although renal hemodynamic factors play a large role in initiating ARF, they are not the dominant determinants of cell damage

  34. ARF - Pathophysiology • Damage is caused mostly by renal perfusion problems and tubular dysfunction • Usual causes • Hypo-perfusion and ischemia • Toxin mediated • Inflammation

  35. ARF – Pathophysiology • Hypo-perfusion • Well perfused kidney – 90% of blood to cortex • Ischemia – increased blood flow to medulla • Outcome may be able to be influenced by restoration of energy/supply demands • Lasix example • Leads to tubular damage

  36. ARF - Pathophysiology • Oxidative damage • Especially during reperfusion injuries • Main players • Super-oxide anion, hydroxyl radical – highly ionizing • Hydrogen peroxide, hypochlorous acid – not as reactive, but because of that have a longer half life and can travel farther and cause injury distal to the site of production

  37. ARF - Pathophysiology • Ischemia • Damage to mitochondrial membrane and change of xanthine dehydrogenase (NAD carrier) to xanthine oxidase (produces O2 radicals) • Profound utilization of ATP  5-10 minutes of ischemia you use ~90% of your ATP • Make lots of adenosine, inosine, hypoxanthine

  38. ATP ADP AMP Adenylosuccinate Adenosine Hypoxanthine IMP Inosine H20 ∙ O2 H2O2 Xanthine H20 ∙ O2 H2O2 Uric Acid H20 ∙ O2 CO2 Allantoin

  39. ARF - Pathophysiology • Once you get reperfusion, the hypoxanthine gets metabolized to xanthine and uric acid – each creating one H2O2 and one super-oxide radical intermediate • Reactive oxygen species oxidize cellular proteins resulting in: • Change in function/inactivation/activation • Loss of structural integrity • Lipid peroxidation (leads to more radical formation) • Direct DNA damage

  40. ARF Pathophysiology • Amount of damage depends on ability to replete ATP stores • Continued low ATP leads to disruption of cell cytoskeleton, increased intracellular Ca, activation of phospholipases and subsequently the apoptotic pathways

  41. Obligatory Incomprehensible Pathway for Jim #2

  42. ARF Pathophysiology • Amount of damage depends on ability to replete ATP stores • Continued low ATP leads to disruption of cell cytoskeleton, increased intracellular Ca, activation of phospholipases and subsequently the apoptotic pathways • This endothelial cell injury sparks an immune response….that can’t be good….

  43. ARF - Prevention • Maintenance of blood flow • Cardiac output, isovolemia, etc • Avoidance of toxins • Aminoglycosides, amphoteracin, NSAIDs • Easy on paper….difficult in practice

  44. ARF - Prevention • Lasix • May have uses early in ARF • Mannitol • May work by • Increasing flow through tubules, preventing obstruction • Osmotic action, decreasing endothelial swelling • Decreased blood viscosity with increased renal perfusion (???) • Free radical scavenging

  45. ARF - Prevention • Renal dose dopamine…. • Endothelin antibodies • No human trials • Thyroxine • More rapid improvement of renal function in animals • Increased uptake of ADP to form ATP or cell membrane stabilization as a possible cause

  46. ARF - Prevention • ANP • Improve renal function and decrease renal insufficiency • ? Nesiritide role • Theophyline • Adenosine antagonist – prevents reduction in GFR. • Growth Factors • After ischemic insult, infusion of IGF-I, Epidermal GF, Hepatocyte GF improved GFR, diminished morphologic injury, diminished mortality • None of these things are well tested…..

  47. ARF – Prevention in Specific Cases • Hemoglobinuria/Myoglobinuria • Mechanism of toxicity • Disassociation to ferrihemate, a tubular toxin, in acidic urine • Tubular obstruction • Inhibition of glomerular flow by PGE inhibition or increased renin activation • Treatments (?) • Aggressive hydration to increase UOP • Alkalinization of urine • Mannitol/Furosemide to increase UOP • ?Early Hemofiltration

  48. ARF – Prevention in Specific Cases • Uric Acid Nephropathy • A thing of the past thanks to Rasburicase? • Treatments • Aggressive hydration to drive UOP • Alkalinization of the urine • Xanthine oxidase inhibitors

  49. ARF - Management • Electrolyte management • Sodium • Hyponatremia – fluid restriction first, 3% NaCl if AMS or seizing • Potassium • Calcium/Bicarb/Glucose/Insulin/Kayexalate • Hemodialysis